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201.
Bjarne Brudeli Kjetil Wessel Andressen Lise Román Moltzau Nils Olav Nilsen Finn Olav Levy Jo Klaveness 《Bioorganic & medicinal chemistry》2013,21(22):7134-7145
Serotonin (5-hydroxytryptamine, 5-HT) is an important signaling molecule in the central nervous system (CNS) and in non-neuronal tissues and organs. Serotonin mediates a positive chronotropic and inotropic response through 5-HT4 receptors in the atrium and ventricle of the heart. Recent investigations have revealed increased expression of the 5-HT4(b) isoform in cardiomyocytes of chronic arrhythmic and failing hearts, and that the use of 5-HT4 receptor antagonists may be beneficial for treating these conditions. The 5-HT4 receptor possesses a transmembrane (TM) binding site important for ligand affinity and recognition, as well as a capacity to accommodate bulky ligands. A new series of peripherally-acting 5-HT4 receptor antagonists were prepared by combining the acidic biphenyl group from the class of angiotensin II receptor blockers (ARBs) with the SB207266 (piboserod) scaffold. The new compounds were pharmacologically evaluated and carboxylic acid 21 was identified as a potent and promising 5-HT4 receptor antagonist with moderate affinity for the AT1 receptor. The permeability of carboxylic acid 21 in a Caco-2 assay was low and the corresponding prodrug esters 23a–f were therefore prepared. The pharmacokinetics of methyl ester 20 and n-butyl ester 23c were evaluated in a rat model, revealing incomplete metabolism to carboxylic acid 21. However, methyl ester 20 is a potent 5-HT4 receptor antagonist with binding affinities in the low picomolar range. Methyl ester 20 has promising oral bioavailability and pharmacokinetics and may target 5-HT4 receptors in both CNS and peripheral organs. 相似文献
202.
Stefan Reschke Kajsa G. V. Sigfridsson Paul Kaufmann Nils Leidel Sebastian Horn Klaus Gast Carola Schulzke Michael Haumann Silke Leimkühler 《The Journal of biological chemistry》2013,288(41):29736-29745
The molybdenum cofactor is an important cofactor, and its biosynthesis is essential for many organisms, including humans. Its basic form comprises a single molybdopterin (MPT) unit, which binds a molybdenum ion bearing three oxygen ligands via a dithiolene function, thus forming Mo-MPT. In bacteria, this form is modified to form the bis-MPT guanine dinucleotide cofactor with two MPT units coordinated at one molybdenum atom, which additionally contains GMPs bound to the terminal phosphate group of the MPTs (bis-MGD). The MobA protein catalyzes the nucleotide addition to MPT, but the mechanism of the biosynthesis of the bis-MGD cofactor has remained enigmatic. We have established an in vitro system for studying bis-MGD assembly using purified compounds. Quantification of the MPT/molybdenum and molybdenum/phosphorus ratios, time-dependent assays for MPT and MGD detection, and determination of the numbers and lengths of Mo–S and Mo–O bonds by X-ray absorption spectroscopy enabled identification of a novel bis-Mo-MPT intermediate on MobA prior to nucleotide attachment. The addition of Mg-GTP to MobA loaded with bis-Mo-MPT resulted in formation and release of the final bis-MGD product. This cofactor was fully functional and reconstituted the catalytic activity of apo-TMAO reductase (TorA). We propose a reaction sequence for bis-MGD formation, which involves 1) the formation of bis-Mo-MPT, 2) the addition of two GMP units to form bis-MGD on MobA, and 3) the release and transfer of the mature cofactor to the target protein TorA, in a reaction that is supported by the specific chaperone TorD, resulting in an active molybdoenzyme. 相似文献
203.
Lehtihet M Welsh N Berggren PO Cook GA Sjoholm A 《American journal of physiology. Endocrinology and metabolism》2003,285(2):E438-E446
Hypoglycemic sulfonylureas such as glibenclamide have been widely used to treat type 2 diabetic patients for 40 yr, but controversy remains about their mode of action. The widely held view is that they promote rapid insulin exocytosis by binding to and blocking pancreatic beta-cell ATP-dependent K+ (KATP) channels in the plasma membrane. This event stimulates Ca2+ influx and sets in motion the exocytotic release of insulin. However, recent reports show that >90% of glibenclamide-binding sites are localized intracellularly and that the drug can stimulate insulin release independently of changes in KATP channels and cytoplasmic free Ca2+. Also, glibenclamide specifically and progressively accumulates in islets in association with secretory granules and mitochondria and causes long-lasting insulin secretion. It has been proposed that nutrient insulin secretagogues stimulate insulin release by increasing formation of malonyl-CoA, which, by blocking carnitine palmitoyltransferase 1 (CPT-1), switches fatty acid (FA) catabolism to synthesis of PKC-activating lipids. We show that glibenclamide dose-dependently inhibits beta-cell CPT-1 activity, consequently suppressing FA oxidation to the same extent as glucose in cultured fetal rat islets. This is associated with enhanced diacylglycerol (DAG) formation, PKC activation, and KATP-independent glibenclamide-stimulated insulin exocytosis. The fat oxidation inhibitor etomoxir stimulated KATP-independent insulin secretion to the same extent as glibenclamide, and the action of both drugs was not additive. We propose a mechanism in which inhibition of CPT-1 activity by glibenclamide switches beta-cell FA metabolism to DAG synthesis and subsequent PKC-dependent and KATP-independent insulin exocytosis. We suggest that chronic CPT inhibition, through the progressive islet accumulation of glibenclamide, may explain the prolonged stimulation of insulin secretion in some diabetic patients even after drug removal that contributes to the sustained hypoglycemia of the sulfonylurea. 相似文献
204.
A method for the rapid electrophoresis on a cellulose acetate membrane of serum proteins from horses, sheep and pigs is discussed. The various main globulin fractions in the serum of these animals were experimentally identified. Normal values for the percentage composition of serum from normal horses, sheep and pigs were calculated. In the horse there was great individual variation in the shape of the β-fraction, assumed to be due to different transferrin types. The mean value for β-globulin of 19.5 % in the horse was higher than for the other two species. The albumin percentage was highest in the sheep and lowest in the pig, 48.5 % and 43.2 % respectively. The sheep had the highest γ-globulin percentage, 22.8 %, while the horse had the lowest with 19.0 %. Finally the values were compared with corresponding figures reported by other authors and the results discussed. 相似文献
205.
Multiplex sequencing of bacterial artificial chromosomes for assembling complex plant genomes 下载免费PDF全文
Sebastian Beier Axel Himmelbach Thomas Schmutzer Marius Felder Stefan Taudien Klaus F. X. Mayer Matthias Platzer Nils Stein Uwe Scholz Martin Mascher 《Plant biotechnology journal》2016,14(7):1511-1522
Hierarchical shotgun sequencing remains the method of choice for assembling high‐quality reference sequences of complex plant genomes. The efficient exploitation of current high‐throughput technologies and powerful computational facilities for large‐insert clone sequencing necessitates the sequencing and assembly of a large number of clones in parallel. We developed a multiplexed pipeline for shotgun sequencing and assembling individual bacterial artificial chromosomes (BACs) using the Illumina sequencing platform. We illustrate our approach by sequencing 668 barley BACs (Hordeum vulgare L.) in a single Illumina HiSeq 2000 lane. Using a newly designed parallelized computational pipeline, we obtained sequence assemblies of individual BACs that consist, on average, of eight sequence scaffolds and represent >98% of the genomic inserts. Our BAC assemblies are clearly superior to a whole‐genome shotgun assembly regarding contiguity, completeness and the representation of the gene space. Our methods may be employed to rapidly obtain high‐quality assemblies of a large number of clones to assemble map‐based reference sequences of plant and animal species with complex genomes by sequencing along a minimum tiling path. 相似文献
206.
PTPRN2 and PLCβ1 promote metastatic breast cancer cell migration through PI(4,5)P2‐dependent actin remodeling 下载免费PDF全文
Caitlin A Sengelaub Kristina Navrazhina Jason B Ross Nils Halberg Sohail F Tavazoie 《The EMBO journal》2016,35(1):62-76
Altered abundance of phosphatidyl inositides (PIs) is a feature of cancer. Various PIs mark the identity of diverse membranes in normal and malignant cells. Phosphatidylinositol 4,5‐bisphosphate (PI(4,5)P2) resides predominantly in the plasma membrane, where it regulates cellular processes by recruiting, activating, or inhibiting proteins at the plasma membrane. We find that PTPRN2 and PLCβ1 enzymatically reduce plasma membrane PI(4,5)P2 levels in metastatic breast cancer cells through two independent mechanisms. These genes are upregulated in highly metastatic breast cancer cells, and their increased expression associates with human metastatic relapse. Reduction in plasma membrane PI(4,5)P2 abundance by these enzymes releases the PI(4,5)P2‐binding protein cofilin from its inactive membrane‐associated state into the cytoplasm where it mediates actin turnover dynamics, thereby enhancing cellular migration and metastatic capacity. Our findings reveal an enzymatic network that regulates metastatic cell migration through lipid‐dependent sequestration of an actin‐remodeling factor. 相似文献
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209.
In the present study, we microinjected fluorescently labelled liver bovine ACBP (acyl-CoA-binding protein) [FACI-50 (fluorescent acyl-CoA indicator-50)] into HeLa and BMGE (bovine mammary gland epithelial) cell lines to characterize the localization and dynamics of ACBP in living cells. Results showed that ACBP targeted to the ER (endoplasmic reticulum) and Golgi in a ligand-binding-dependent manner. A variant Y28F/K32A-FACI-50, which is unable to bind acyl-CoA, did no longer show association with the ER and became segregated from the Golgi, as analysed by intensity correlation calculations. Depletion of fatty acids from cells by addition of FAFBSA (fatty-acid-free BSA) significantly decreased FACI-50 association with the Golgi, whereas fatty acid overloading increased Golgi association, strongly supporting that ACBP associates with the Golgi in a ligand-dependent manner. FRAP (fluorescence recovery after photobleaching) showed that the fatty-acid-induced targeting of FACI-50 to the Golgi resulted in a 5-fold reduction in FACI-50 mobility. We suggest that ACBP is targeted to the ER and Golgi in a ligand-binding-dependent manner in living cells and propose that ACBP may be involved in vesicular trafficking. 相似文献
210.
Roger L. H. Dennis Leonardo Dapporto Tim G. Shreeve Eddie John John G. Coutsis Otakar Kudrna Kimmo Saarinen Nils Ryrholm W. R. Williams 《Journal of Insect Conservation》2008,12(3-4):205-236
Depending on their faunal content islands can function as important ‘vehicles’ for conservation. In this study, we examine data on 440 butterfly species over 564 European islands in 10 island groups. To determine the status of the butterfly fauna, we have adopted two approaches, island-focused and species-focused, examined using principal components analysis and regression modelling. In the former, we relate species richness, rarity and endemicity to island geography (area, elevation, isolation and location in latitude and longitude); in the latter, species occurrence on islands is examined in relation to distribution, range, range boundaries, and altitudinal limits on the continent as well as species’ ecology (number of host plants) and morphology (wing expanse). Species on islands are also assessed for their status on the continental mainland, their distributional dynamics (extinctions, distribution changes) and conservation status (Red Data Book, European Habitat Directive, Species of European Conservation Concern and Bern Convention listing. Unexpectedly, we find that a large fraction of the European butterfly species is found on the islands (63.4%; 59% on small islands) comprising some 6.2% of the land area of Europe. Although species occurring on the islands tend, on the whole, to have lower conservation status and are not declining over Europe, 45 species are endemics restricted to the islands. Species richness shows only a weak locational pattern and is related as expected to isolation from the continental source and island area; but, both rarity and endemicity have distinctive geographical bias to southern Europe, on islands now under increasing pressure from climate change and increasingly intensive human exploitation. The vulnerability of species on islands is emphasised in the relationship of island occurrence (% occurrence and presence/absence of species on any island) with continental distributions. A large proportion of the variation (84%) is accounted by continental distribution, the southern range limit and lower altitudinal limit. Most species (69%) occur on very few islands (<5%). In view of ongoing species dynamics on islands, migrations and extinctions of species, island repositories of species depend in large part on conservation of butterflies at continental sources. The unique faunas and rare species on islands also depend on appropriate concern being given to the island faunas. Conservation of European islands is thus a two-way process, sustaining sources and conserving island refuges. Residuals from the regressions (islands with more or fewer species, rare and endemic species; species occurring more or less frequently than expected on islands) provide warning signals of regions and islands deserving immediate attention. 相似文献